Histoplasmosis is a respiratory fungal disease with significant morbidity and mortality, and also has been recently recognized with increasing frequency in patients with acquired immunodeficiency syndrome (AIDS). The infection is acquired by inhalation of Histoplasma capsulatum (HC) and the organism disseminates to extrapulmonary sites by both lymphatic and blood streams. How the organism crosses the lymphatic and blood vessels is not known. The overall objective of the proposed research is to study the interactions of human umbilical and pulmonary vessel endothelial cells (EC) with yeast cells of Histoplasma. Human umbilical and pulmonary endothelial cell cultures will be exposed to live and killed yeast cells of HC. For comparison, parallel EC cultures will be exposed to live and killed Torulopsis glabrata (TG), an opportunistic fungus, chosen for its size proximity to HC yeast cells. Morphological characteristics of the adherence, and any damage to the effector and target cells will be determined by light and electron microscopy. Alteration of cellular integrity and metabolic functions of the EC will be determined by measuring angiotensin converting enzymes, 51Cr release from radiolabelled EC and the cell products thromboxane A2 and prostacyclin. In an attempt to mimic the in vivo situation, we will study the interactions of HC with endothelial cells attached to the umbilical cord vein and pulmonary vessel intimal explants placed in chemotaxis chambers. The possibility of extrapulmonary dissemination of Histoplasma within phagocytic macrophages will be tested by determining the migration of HC infected and uninfected human monocytes through intact endothelium in intimal explants. It is anticipated that the results of the proposed study will provide valuable information on understanding the mechanism involved in the extravascular dissemination of the organism and the role of endothelial cells in pathogenesis of histoplasmosis.